Freeze drying is a process that removes a solvent, typically water, from a product in the form of ice. While water is used in the present disclosure as the exemplary solvent, other solvents, such as alcohol, are also used in freeze drying processes and may be used with the presently disclosed methods and apparatus. In the freeze drying process, the product is frozen and, under vacuum, the ice sublimes and the vapor flows towards a condenser. The water or other solvent is condensed on the condenser as ice and is removed in a later stage. Freeze drying is particularly useful in the pharmaceutical industry, as the integrity of the product is preserved during the freeze drying process and product stability can be guaranteed over relatively long periods of time. The freeze dried product is ordinarily a biological substance and is commonly contained in vials.
As illustrated by the example freeze drying system 100 of FIG. 1, a batch of product 112 is placed on freeze dryer shelves 121 within a freeze drying chamber 110. The freeze dryer shelves 121 are hollow and are used to support the product and to transfer heat to and from the product as required by the process. A heat transfer fluid 114 flows through the shelves to remove or add heat.
Water vapor created by the sublimation of ice in the product 112 flows through a passageway 115 into a condensing chamber 120 containing condensing coils or other surfaces 122 maintained below the condensation temperature. A coolant 125 is passed through the coils 122 to remove heat, causing the water vapor to condense as ice on the coils.
Both the freeze drying chamber 110 and the condensing chamber 120 are maintained under vacuum during the process by a vacuum pump 150 having a low pressure inlet 151 connected to the exhaust of the condensing chamber 120. Non-condensable gases contained in the chambers 110, 120 are removed by the vacuum pump 150 and exhausted at a high pressure outlet 152.
Pharmaceutical freeze drying is an aseptic process that requires sterile conditions within the freeze drying chamber 110 and condenser chamber 120. A freeze drying cycle may last several days, and the quantity of product processed in a single batch may represent a very large investment. It is therefore critical to assure that the freeze drying system is sterile and leak-free before a cycle is commenced and for the duration of the cycle. Both the shelves in the freeze drying chamber and the coils in the condensing chamber are hollow, and contain heat transfer media. It is important to be able to detect any leakage of those non-sterile fluids into the process vessels should a leak occur.
In the condenser, the coolant media used may be of a very low viscosity, and have a low vapor pressure, making detection of a leak difficult. In the case of a condenser circuit that is cooled by direct expansion of a refrigerant, leakage of the gaseous refrigerant is also difficult to detect and is undesirable in the freeze drying process. In the freeze drying chamber, the hollow shelves are flushed by thermal fluid that is typically a silicone oil of very low viscosity. Those silicone oils also have a very low vapor pressure, making it very difficult to detect leakage. Therefore there is a need for leak detection, preferably real time, without disturbing the aseptic freeze drying process.
The chambers and connecting passages are under vacuum and are therefore required to maintain a high pressure differential across their walls. Any leakage of non-sterile ambient gases through the walls into the aseptic chambers must be detected as quickly and accurately as possible.
It has been proposed to perform a secondary drying operation wherein the condensing chamber 120 is temporarily bypassed by a passageway 130 in a final drying stage to remove small amounts of residual moisture. In the secondary drying operation, a small amount of residual water vapor from the product passes through the vacuum pump 150 and is contained in the vacuum pump exhaust. The secondary drying process is conceptually limited by the capacity of the vacuum pump to pump water vapor. One expected problem in performing a secondary drying operation is the adequate detection or measurement of moisture content in the product, for monitoring the progress of the operation. A system is needed for measuring water removal without interfering with the pharmaceutical drying process.
Most freeze dryer diagnostic techniques are direct, and analyze the condition of the gas in the drying chamber. Direct checking of leakage may be complicated with very large freeze dryers, where manual checking cannot be done. Further, if the leakage is related to certain time periods in the freeze-drying cycle, or related to certain high or low temperatures, the likelihood of detection might be minimal.
Examples of such in-situ low pressure analysis techniques are residual gas analysis using mass spectroscopy, and partial pressure gas analysis, for which there are many specialized methods. Several disadvantages are inherent in those technologies. The measurements of interest are taken at low pressure, meaning low concentrations that result in detection difficulties. Moreover, the gas streams within the freeze drying chamber and the condensation chamber contain a large amount of water (99%) from the drying process, which may overwhelm the measurement of other species.
The measurement technologies may interfere with the drying process. Those in-situ low-pressure detection technologies must, by nature, sample the gas flow within the sterile environment where freeze drying takes place. Many of those technologies, however, involve sensors that are not easily sterilized. Some of those technologies even create byproducts such as chemically reactive species that may affect the material that is being dried in unfavorable ways.
There is therefore a need for a technique for effectively monitoring a freeze drying process without disturbing the normal process routine. The technique should be easily automated, should not introduce contaminants into the process, and should detect, with high accuracy, leaks or other abnormalities in the process.